The present invention relates to an oral pharmaceutical formulation comprising the acid labile H+, K+-ATPase inhibitor omeprazole, an alkaline salt of omeprazole, one of the single enantiomers thereof or an alkaline salt of one of the single enantiomers of omeprazole. In the following these compounds are referred to as omeprazole. The formulation is in the form of a multiple unit dosage form that comprises enteric coating layered units of omeprazole. More specifically, the units comprise a core material that comprises omeprazole optionally in admixture with an alkaline reacting substance, and in admixture with one or more pharmaceutically acceptable excipients such as a binding agent, a filling agent and/or a disintegrating agent. Furthermore, each unit comprises a separating layer to separate the enteric coating layer from the core material. The separating layer comprises a specific quality of hydroxypropyl cellulose (HPC), and optionally pharmaceutical excipients. More specifically, the HPC quality is defined by having a specific cloud point.
Furthermore, the present invention refers to the use of the specific quality of HPC in the manufacture of a pharmaceutical formulation comprising omeprazole, and the use of such a pharmaceutical formulation in medicine.
Omeprazole, an alkaline salt thereof, the single enantiomers of omeprazole and an alkaline salt of the single enantiomers of omeprazole, all compounds hereinafter referred to as omeprazole, are used in the treatment of gastric acid related diseases. Omeprazole and pharmaceutically acceptable salts thereof are described in EP 5129, and some specific alkaline salts of omeprazole are described in EP 124 495 and W095/01977. Certain salts of the single enantiomers of omeprazole and their preparations are described in WO94/27988.
Omeprazole is generally known to be useful for inhibiting gastric acid secretion in mammals and man by controlling gastric acid secretion at the final step of the acid secretory pathway. Thus, in a more general sense, it may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcers and duodenal ulcers. Furthermore, it may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with non ulcer dyspepsia, in patients with symptomatic gastro-oesophageal reflux disease, and in patients with gastrinomas. It may also be used in a patient in intensive care situations, in a patient with acute upper gastrointestinal bleeding, pre-and post-operatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, it may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these, as well as in the treatment or prophylaxis of inflammatory conditions in mammals, including man.
Omeprazole is, however, susceptible to degradation or transformation in acidic and neutral media. The degradation is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The chemical stability of omeprazole is also affected by moisture, heat, and organic solvents and to some degree by light.
Due to the chemical stability properties of omeprazole, it is obvious that an oral solid dosage form comprising omeprazole must be protected from contact with the acidic gastric juice. Omeprazole must also be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption can occur.
A pharmaceutical oral dosage form of omeprazole is best protected from contact with acidic gastric juice by an enteric coating layer. For instance, EP 247 983 describes enteric coated formulations of omeprazole. Such as formulation contains omeprazole in the form of a core unit containing omeprazole together with an alkaline salt or containing an alkaline salt of omeprazole optionally together with an alkaline salt, the core unit is layered with a separating layer and an enteric coating layer. In WO 96/01623 a multiple unit tableted dosage formulation comprising omeprazole is described.
The oral formulations described in EP 247 983 and the tablet formulations described in WO 96/01623 are examples of enteric coating layered formulations that comprise or optionally comprise a separating layer to separate the acidic enteric coating material from omeprazole being an acid susceptible substance. HPC may be used in a layer that separates the core material from the enteric coating layer in the described formulations. All ingredients, including HPC qualities, used in a pharmaceutical preparation must fulfil strict criteria, such as for instance requirements defined in pharmacopoeial monographs.
The rate of release of omeprazole from a pharmaceutical dosage form can influence the total extent of absorption of omeprazole into the general circulation (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120). Therefore the limits for rate of release of the omeprazole from the pharmaceutical formulation are stated in the marketing approval for the products. The release of omeprazole is affected both by the chemical stability of the active substance and the release stability of the pharmaceutical formulation. If the formulation is unstable with respect to the release rate, the drug will have a non-accepted storage time, i.e. the expiration period for the product will be too short.
It has now surprisingly been found that different batches of HPC, which fulfil all pharmacopoeial requirements, used as material for the separating layer in a pharmaceutical formulation comprising omeprazole, may result in different release rate over time. Thus, the storage period for the pharmaceutical formulation may not be acceptable. One parameter of interest for the HPC""s influence on the release stability is its water solubility.
The aqueous solubility of HPC decreases with increasing temperature due to polymer phase separation. This is observed as a clouding of the polymer solution when the temperature is increased. Cloud point is the temperature at which this polymer phase separation occurs. Cloud point is determined by measuring the light transmission through the polymer solution. The light transmission of a specific system where the polymer is dissolved, that is a transparent polymer solution without clouding, is defined as light transmission 100%. In this patent application cloud point is defined as the temperature where the light transmission of a specific system is 96% when a commercial instrument from Mettler is used. For other cloud point systems and instruments another light transmisson may be specified for each system.
One problem that can be avoided by the new formulation and use of a specific quality of HPC, is that the storage period for the dosage form can be extended and guarantied. From an economical aspect it is advantageous to specify and check the HPC quality thereby keeping a long expire date of the dosage form.
It has now been found that a quality of HPC with a cloud point of not less than 38xc2x0 C. determined as the temperature where the light transmission of a specified system is 96% measured by a Mettler FP90/FP 81C instrument is desirable in an enteric coating layered pharmaceutical formulation comprising omeprazole. Preferably, the HPC should have a cloud point of not less than 40xc2x0 C., and more preferably not less than 41xc2x0 C. When another instrument is used for determination, the cloud point may be specified in other terms. An upper limit for the cloud point is not critical and therefore there is no need to specify that.
The HPC is used as a constituent of a separating layer separating the core material comprising omeprazole from the enteric coating layer. The HPC quality defined in the present patent application is desirable in fulfilling the criteria on release rate stability and to be suitable for oral administration forms comprising omeprazole.